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Doklady Biological Sciences :... Jul 2024Abstract-Carriers of herpes simplex virus type 1 (HSV-1) account for more than 90% of the global population. Infection manifests itself in the formation of blisters and...
Abstract-Carriers of herpes simplex virus type 1 (HSV-1) account for more than 90% of the global population. Infection manifests itself in the formation of blisters and ulcers on the face or genitals and can cause blindness, encephalitis, and generalized infection. All first- and second-line modern antiherpetic drugs selectively inhibit viral DNA polymerase. The purine-benzoxazine conjugate LAS-131 ((S)-4-[6-(purin-6-yl)aminohexanoyl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine), which we have described earlier, uses the large subunit of the HSV-1 terminase complex as a biotarget and selectively inhibits HSV-1 reproduction in vitro. Basically new results were for the first time obtained to characterize the combined effect on human herpesvirus infection for LAS-131 used in combination with practically significant antiviral compounds, including the nucleoside analogs acyclovir (ACV), penciclovir (PCV), ganciclovir (GCV), brivudine (BVdU), iododeoxyuridine (IdU), and adenine arabinoside (Ara-A); the nucleoside phosphonate analog cidofovir (CDV); and the pyrophosphate analog foscarnet (FOS). A cytopathic effect (CPE) inhibition assay showed that the drug concentration that inhibited the virus-induced CPE by 50% decreased by a factor of 2 (an additive effect, FOS) or more (a synergistic effect; ACV, PCV, GCV, IdU, BVdU, Ara-A, and CDV) when the drugs were used in combination with LAS-131. Nonpermissive conditions for HSV-1 reproduction were thus created at lower drug concentrations, opening up new real possibilities to control human herpesvirus infection.
PubMed: 38955885
DOI: 10.1134/S0012496624701035 -
Chemphyschem : a European Journal of... Jul 2024Acetone (CH3COCH3), the simplest ketone, has recently attracted considerable attention for its important role in atmospheric chemistry and in the formation of ices in...
Acetone (CH3COCH3), the simplest ketone, has recently attracted considerable attention for its important role in atmospheric chemistry and in the formation of ices in extraterrestrial sources that contain complex organic molecules. In this study, we employed a combination of experimental rotational spectroscopy and quantum chemistry calculations to investigate the structure and dynamics of the acetone-water complex. Our aim was to understand how non-covalent interactions with water affect the methyl internal rotation dynamics of acetone, and how water-centered large amplitude motions alter the observed physical properties compared to those predicted at the equilibrium position. Detailed rotation-tunneling analyses of acetone-H2O and -D2O reveal that the interactions with water disrupt the equivalence of the two methyl rotors, resulting in a noticeably lower methyl rotor barrier for the top with the close-by water compared to that of free acetone. The barrier for the methyl group further from water is also lower, although to a lesser degree. To gain further insights, extensive theoretical modelling was conducted, focusing on the associated large amplitude motions. Furthermore, quantum theory of atoms in molecules and non-covalent interactions analyses were utilized to visualize the underlying causes of the observed trends.
PubMed: 38955766
DOI: 10.1002/cphc.202400573 -
Genomics, Proteomics & Bioinformatics Jul 2024The development and maturation of follicles is a sophisticated and multistage process. The dynamic gene expression of oocytes and their surrounding somatic cells and the...
The development and maturation of follicles is a sophisticated and multistage process. The dynamic gene expression of oocytes and their surrounding somatic cells and the dialogs between these cells are critical to this process. In this study, we accurately classified the oocyte and follicle development into nine stages and profiled the gene expression of mouse oocytes and their surrounding granulosa cells and cumulus cells. The clustering of the transcriptomes showed the trajectories of two distinct development courses of oocytes and their surrounding somatic cells. Gene expression changes precipitously increased at Type 4 stage and drastically dropped afterward within both oocytes and granulosa cells. Moreover, the number of differentially expressed genes between oocytes and granulosa cells dramatically increased at Type 4 stage, most of which persistently passed on to the later stages. Strikingly, cell communications within and between oocytes and granulosa cells became active from Type 4 stage onward. Cell dialogs connected oocytes and granulosa cells in both unidirectional and bidirectional manners. TGFB2/3, TGFBR2/3, INHBA/B, and ACVR1/1B/2B of TGF-β signaling pathway functioned in the follicle development. NOTCH signaling pathway regulated the development of granulosa cells. Additionally, many maternally DNA methylation- or H3K27me3-imprinted genes remained active in granulosa cells but silent in oocytes during oogenesis. Collectively, Type 4 stage is the key turning point when significant transcription changes diverge the fate of oocytes and granulosa cells, and the cell dialogs become active to assure follicle development. These findings shed new insights on the transcriptome dynamics and cell dialogs facilitating the development and maturation of oocytes and follicles.
Topics: Animals; Female; Oocytes; Mice; Granulosa Cells; Transcriptome; Ovarian Follicle; Cell Communication; Signal Transduction; Gene Expression Profiling; DNA Methylation; Oogenesis
PubMed: 38955498
DOI: 10.1093/gpbjnl/qzad001 -
Metallomics : Integrated Biometal... Jul 2024Both 8-hydroxyquinoline compounds and iridium (Ir) complexes have emerged as potential novel agents for tumor therapy. In this study, we synthesized and characterized...
Both 8-hydroxyquinoline compounds and iridium (Ir) complexes have emerged as potential novel agents for tumor therapy. In this study, we synthesized and characterized two new Ir(III) complexes, [Ir(L1)(bppy)2] (Br-Ir) and [Ir(L2)(bppy)2] (Cl-Ir), with 5,7-dibromo-2-methyl-8-hydroxyquinoline (HL-1) or 5,7-dichloro-2-methyl-8-hydroxyquinoline (HL-2) as the primary ligand. Complexes Br-Ir and Cl-Ir successfully inhibited antitumor activity in Hep-G2 cells. In addition, complexes Br-Ir and Cl-Ir were localized in the mitochondrial membrane and caused mitochondrial damage, autophagy, and cellular immunity in Hep-G2 cells. We tested the proteins related to mitochondrial and mitophagy by western blot analysis, which showed that they triggered mitophagy-mediated apoptotic cell death. Remarkably, complex Br-Ir showed high in vivo antitumor activity, and the tumor growth inhibition rate (IR) was 63.0% (p <0.05). In summary, our study on complex Br-Ir revealed promising results in in vitro and in vivo antitumor activity assays.
PubMed: 38955388
DOI: 10.1093/mtomcs/mfae032 -
Cell Reports. Medicine Jun 2024Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of...
Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 μg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 μg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).
PubMed: 38955178
DOI: 10.1016/j.xcrm.2024.101630 -
Journal of Breath Research Jul 2024Preservation of the breath sample integrity during storage and transport is one of biggest challenges in off-line exhaled breath gas analysis. In this context, adsorbent...
Preservation of the breath sample integrity during storage and transport is one of biggest challenges in off-line exhaled breath gas analysis. In this context, adsorbent tubes are frequently used as storage containers for use with analytical methods employing gas chromatography with mass spectrometric detection. The key objective of this short communication is to provide data on the recovery of selected breath volatiles from Tenax® TA adsorbent tubes that were stored at -80 C for up to 90 days. For this purpose, an Owlstone Medical's ReCIVA® Breath Sampler was used for exhaled breath collection. The following fifteen compounds, selected to cover a range of chemical properties, were monitored for their stability: isoprene, n-heptane, n-nonane, toluene, p-cymene, allyl methyl sulfide, 1-(methylthio)-propane, 1-(methylthio)-1-propene, -pinene, DL-limonene, β-pinene, -terpinene, 2-pentanone, acetoin and 2,3 butanedione. All compounds but one (acetoin) were found to be stable during the first 4 weeks of storage (recovery within 2×RSD). Furthermore, n-nonane was stable during the whole of the investigated period.
PubMed: 38955168
DOI: 10.1088/1752-7163/ad5dee -
Pathology, Research and Practice Jun 2024Cancer is a serious disease that can affect various parts of the body such as breast, colon, lung or stomach. Each of these cancers has their own treatment dependent...
Cancer is a serious disease that can affect various parts of the body such as breast, colon, lung or stomach. Each of these cancers has their own treatment dependent historical subgroups. Hence, the correct identification of cancer subgroup has almost same importance as the timely diagnosis of cancer. This is still a challenging task and a system with highest accuracy is essential. Current researches are moving towards analyzing the gene expression data of cancer patients for various purposes including biomarker identification and studying differently expressed genes, using gene expression data measured in a single level (selected from different gene levels including genome, transcriptome or translation). However, previous studies showed that information carried by one level of gene expression is not similar to another level. This shows the importance of integrating multi-level omics data in these studies. Hence, this study uses tumor gene expression data measured from various levels of gene along with the integration of those data in the subgroup classification of nine different cancers. This is a comprehensive analysis where four different gene expression data such as transcriptome, miRNA, methylation and proteome are used in this subgrouping and the performances between models are compared to reveal the best model.
PubMed: 38955118
DOI: 10.1016/j.prp.2024.155419 -
Redox Biology Jun 2024Ferroptosis is a form of iron-related oxidative cell death governed by an integrated redox system, encompassing pro-oxidative proteins and antioxidative proteins. These... (Review)
Review
Ferroptosis is a form of iron-related oxidative cell death governed by an integrated redox system, encompassing pro-oxidative proteins and antioxidative proteins. These proteins undergo precise control through diverse post-translational modifications, including ubiquitination, phosphorylation, acetylation, O-GlcNAcylation, SUMOylation, methylation, N-myristoylation, palmitoylation, and oxidative modification. These modifications play pivotal roles in regulating protein stability, activity, localization, and interactions, ultimately influencing both the buildup of iron and lipid peroxidation. In mammalian cells, regulators of ferroptosis typically undergo degradation via two principal pathways: the ubiquitin-proteasome system, which handles the majority of protein degradation, and autophagy, primarily targeting long-lived or aggregated proteins. This comprehensive review aims to summarize recent advances in the post-translational modification and degradation of proteins linked to ferroptosis. It also discusses strategies for modulating ferroptosis through protein modification and degradation systems, providing new insights into potential therapeutic applications for both cancer and non-neoplastic diseases.
PubMed: 38955112
DOI: 10.1016/j.redox.2024.103259 -
Archives of Medical Research Jul 2024Health problems associated with aging are a major public health concern for the future. Aging is a complex process with wide intervariability among individuals.... (Review)
Review
Health problems associated with aging are a major public health concern for the future. Aging is a complex process with wide intervariability among individuals. Therefore, there is a need for innovative public health strategies that target factors associated with aging and the development of tools to assess the effectiveness of these strategies accurately. Novel approaches to measure biological age, such as epigenetic clocks, have become relevant. These clocks use non-sequential variable information from the genome and employ mathematical algorithms to estimate biological age based on DNA methylation levels. Therefore, in the present study, we comprehensively review the current status of the epigenetic clocks and their associations across the human phenome. We emphasize the potential utility of these tools in an epidemiological context, particularly in evaluating the impact of public health interventions focused on promoting healthy aging. Our review describes associations between epigenetic clocks and multiple traits across the life and health span. Additionally, we highlighted the evolution of studies beyond mere associations to establish causal mechanisms between epigenetic age and disease. We explored the application of epigenetic clocks to measure the efficacy of interventions focusing on rejuvenation.
PubMed: 38955096
DOI: 10.1016/j.arcmed.2024.103033 -
Inorganic Chemistry Jul 2024Reactions in water between a lanthanide ion and 3,4,5,6-tetrachloro-phthalate lead to a new series of iso-structural coordination polymers with general chemical formula...
Reactions in water between a lanthanide ion and 3,4,5,6-tetrachloro-phthalate lead to a new series of iso-structural coordination polymers with general chemical formula [Ln(tcpa)(HO)] with Ln = Eu-Yb plus Y. The crystal structure has been solved on the Y-derivative. This compound crystallizes in the monoclinic system, space group 2/ (no. 14) with the following cell parameters: = 6.2155(2) Å, = 19.6652(7) Å, = 30.3720(9) Å, β = 94.631(1)°, = 3700.22(37) Å, and = 4. Luminescence properties of homo- and heterolanthanide coordination polymers that belong to this structural family have been studied in detail. This study shows that, in this system, intermetallic energy transfers are very efficient and that dilution by an optically non active Gd ion leads to quite efficient luminescent heterolanthanide coordination polymers. The luminescence of these compounds, dispersed at a low doping rate in a poly(methyl methacrylate) (PMMA) matrix, can be observed even with the naked eye. This study opens the way to the use of such compounds as taggants for optical sorting of plastic waste and consecutive recycling.
PubMed: 38954824
DOI: 10.1021/acs.inorgchem.4c01866